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International journal of molecular sciences
Sep 23, 2020;21 (19):

Structure-Based Discovery of Novel Chemical Classes of Autotaxin Inhibitors.

Christiana Magkrioti, Eleanna Kaffe, Elli-Anna Stylianaki, Camelia Sidahmet, Georgia Melagraki, Antreas Afantitis, Alexios N Matralis, Vassilis Aidinis
Author Information
  1. Christiana Magkrioti: Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Fleming 34, 16672 Athens, Greece.
  2. Eleanna Kaffe: Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Fleming 34, 16672 Athens, Greece.
  3. Elli-Anna Stylianaki: Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Fleming 34, 16672 Athens, Greece.
  4. Camelia Sidahmet: Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Fleming 34, 16672 Athens, Greece. ORCID
  5. Georgia Melagraki: NovaMechanics Ltd, Princess De Tyras 16, 1065 Nicosia, Cyprus.
  6. Antreas Afantitis: NovaMechanics Ltd, Princess De Tyras 16, 1065 Nicosia, Cyprus. ORCID
  7. Alexios N Matralis: Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Fleming 34, 16672 Athens, Greece.
  8. Vassilis Aidinis: Institute for Bioinnovation, Biomedical Sciences Research Center Alexander Fleming, Fleming 34, 16672 Athens, Greece. ORCID
PMID: 32977539 DOI: 10.3390/ijms21197002

Abstract

Autotaxin (ATX) is a secreted glycoprotein, widely present in biological fluids, largely responsible for extracellular lysophosphatidic acid (LPA) production. LPA is a bioactive growth-factor-like lysophospholipid that exerts pleiotropic effects in almost all cell types, exerted through at least six G-protein-coupled receptors (LPAR1-6). Increased ATX expression has been detected in different chronic inflammatory diseases, while genetic or pharmacological studies have established ATX as a promising therapeutic target, exemplified by the ongoing phase III clinical trial for idiopathic pulmonary fibrosis. In this report, we employed an in silico drug discovery workflow, aiming at the identification of structurally novel series of ATX inhibitors that would be amenable to further optimization. Towards this end, a virtual screening protocol was applied involving the search into molecular databases for new small molecules potentially binding to ATX. The crystal structure of ATX in complex with a known inhibitor (HA-155) was used as a molecular model docking reference, yielding a priority list of 30 small molecule ATX inhibitors, validated by a well-established enzymatic assay of ATX activity. The two most potent, novel and structurally different compounds were further structurally optimized by deploying further in silico tools, resulting to the overall identification of six new ATX inhibitors that belong to distinct chemical classes than existing inhibitors, expanding the arsenal of chemical scaffolds and allowing further rational design.

Keywords

ATX inhibitors atotaxin in silico screening small molecules

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Grants

  1. T1EDK-00949/

MeSH Term

Animals
Chronic Disease
Databases, Protein
Enzyme Inhibitors
Humans
Idiopathic Pulmonary Fibrosis
Inflammation
Phosphoric Diester Hydrolases
Small Molecule Libraries
Structure-Activity Relationship

Chemicals

Enzyme Inhibitors
Small Molecule Libraries
Phosphoric Diester Hydrolases
alkylglycerophosphoethanolamine phosphodiesterase
Journal Article
Article has an altmetric score of 6

Word Cloud

Created with Highcharts 10.0.0ATXinhibitorssilicostructurallysmallAutotaxinLPAsixdifferentidentificationnovelscreeningmolecularnewmoleculeschemicalsecretedglycoproteinwidelypresentbiologicalfluidslargelyresponsibleextracellularlysophosphatidicacidproductionbioactivegrowth-factor-likelysophospholipidexertspleiotropiceffectsalmostcelltypesexertedleastG-protein-coupledreceptorsLPAR1-6IncreasedexpressiondetectedchronicinflammatorydiseasesgeneticpharmacologicalstudiesestablishedpromisingtherapeutictargetexemplifiedongoingphaseIIIclinicaltrialidiopathicpulmonaryfibrosisreportemployeddrugdiscoveryworkflowaimingseriesamenableoptimizationTowardsendvirtualprotocolappliedinvolvingsearchdatabasespotentiallybindingcrystalstructurecomplexknowninhibitorHA-155usedmodeldockingreferenceyieldingprioritylist30moleculevalidatedwell-establishedenzymaticassayactivitytwopotentcompoundsoptimizeddeployingtoolsresultingoverallbelongdistinctclassesexistingexpandingarsenalscaffoldsallowingrationaldesignStructure-BasedDiscoveryNovelChemicalClassesInhibitorsatotaxin

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